Topical effects of absorption enhancing agents on the rectal mucosa of rats in vivo.
In the present study, attempts have been made to assess the effects of cefoxitin formulations with various absorption promoters on mucosal integrity after rectal delivery in rats. Observations were made at 2 and 24 h following drug administration. On macroscopic and histologic evaluation, all drug formulations affected mucosal structure in terms of hyperemia, edema, loss of goblet cell vacuoles, detachment of enterocytes, and increase of the number of inflammatory cells; these effects were not reversible in 24 h. The effects of formulations with MGK (a mixture of glyceryl-1-monooctanoate, glyceryl-1,2-dioctanoate, glyceryl-1,3-dioctanoate, glyceryl trioctanoate, glycerol, and octanoic acid), monoglycerides, 3-amino-1-hydroxypropylidene-1,1-diphosphonate, and 4% (w/v) sodium tauro-24,25-dihydrofusidate (STDHF) tended to exceed those observed with sodium salicylate, medium-chain fatty acids, Azone, and lower STDHF concentrations. The clinically used suppository bases Witepsol H15 and PEG 1540/6000 and indomethacin suppositories also affected mucosal structure. Although the interanimal variability in scores was very substantial, results indicate that rectal absorption enhancement is associated with modification of paracellular transport after detachment of enterocytes. However, the extent of drug absorption enhancement appeared not to be directly related to the extent of mucosal damage.
van Hoogdalem
E J
EJ
Center for Bio-Pharmaceutical Sciences, Sylvius Laboratories, State University of Leiden, The Netherlands.
Vermeij-Kerrs
C
C
de Boer
A G
AG
Breimer
D D
DD
D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D002440:Cefoxitin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005079:Excipients / Q000633:toxicity*; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012007:Rectum / Q000378:metabolism*; D013488:Suppositories
D005079:Excipients; D013488:Suppositories; D002440:Cefoxitin